Field of the Invention
The present invention relates to systems, methods, techniques, and compounds having numerous applications including in research and treatment of portal hypertension and other conditions.
Description of the Related Art
The endothelium plays a central role in the maintenance of vascular homeostasis largely by virtue of its synthesis of nitric oxide (NO). It is now well appreciated that the endothelial isoform of nitric oxide synthase (eNOS) produces endothelium-derived NO. Furthermore, endothelial dysfunction contributes to the development and clinical course of vascular diseases such as pulmonary and portal hypertension, both characterized by reduced NO bioactivity.
(±)3-(4-Chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-(3,4-c)pyridine 3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-(3,4-c)pyridine (cicletanine), a substituted synthetic pyridine developed as an antihypertension agent, has been shown to exert direct relaxant effects on vascular smooth muscle.
We have unexpectedly found that cicletanine has or may have a direct effect on eNOS activity in sinusoidal endothelial cells. We have discovered and demonstrated that cicletanine increases nitric oxide synthase (NOS) activity and NO production in both normal sinusoidal endothelial cells and injured endothelial cells, in part via protein kinase B (Akt) and MAP kinase/Erk signaling. Furthermore, paracrine NO regulates stellate cell contractility and appears to reduce portal pressure.